Nuclear receptor coactivators are a class of coregulator proteins that interact with nuclear receptors to enhance their effects on target gene transcription. Steroid receptor coactivator SRC-3 is a nuclear receptor coactivator in SRC family. Although a lot of developmental and physiological roles of SRC-3 have been discovered from studying the SRC3 (-/-) mice, little is known about the role of SRC-3 in innate immune response. SRC3 (-/-) mice are prone to infection and have scruffy skin and body hair and SRC-3 can work with a number of immune target transcription factors such as peroxisome proliferator-activated receptors (PPARs), glucocorticoid receptor (GR) and NFKB. It suggests that SRC-3 might play some roles in innate immune response. In this study, SRC-3 (-/-) mice are used as a model system to define the physiological role of SRC-3 in lipopolysaccharides (LPS)-induced inflammatory response. The specific aims of this proposal are to: 1. Determine the role of SRC-3 (-/-) hepatocytes in LPS-induced inflammatory response. 2. Determine the role of SRC-3 (-/-) macrophages in LPS-induced inflammatory response. 3. Define the molecular mechanism of anti-inflammatory effects of SRC-3 in macrophages. 4. Determine the role of phosphorylation site Ser847 in SRC-3's anti-inflammatory function. [unreadable] [unreadable]